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Soft drugs based on hydrocortisone: the inactive metabolite approach and its application to steroidal
R J Little1, N Bodor, T Loftsson
1Department of Chemistry, Universidad de los Andes, Mérida, Venezuela. rlittle@ciens.ula.ve
Purpose:
The soft drug approach was applied to the design of analogs of highly potent synthetic steroids but with a metabolically labile ester group which at the same time served as an activating group.
Methods:
Several structural modifications of soft antiinflammatory steroids were synthesized and tested in several assays of biological activity. The hydrolytic stability of the compounds was also determined.
Results:
One of the compounds synthesized was determined to be a very potent steroid and had a highly significant separation of topical from systemic activity. However, the compound demonstrated greater than expected stability in the hydrolysis studies.
Conclusions:
The goal of the soft drug approach has been achieved with the development of a highly potent drug which displays little or no systemic activity as measured in the tests presented here. The anticipated hydrolytic instability of the compounds was not corroborated; however, in view of other results, the interpretation is allowed that the rapid hydrolysis of the unbound fraction of the drug is an important factor in its lack of systemic effects.
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